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9. Modeling Therapeutic Antibody-Small Molecule Drug-Drug Interactions Using a Three-Dimensional Perfusable Human Liver Coculture Platform

Author

Massachusetts Institute of Technology. Biotechnology Process Engineering Center, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Mechanical Engineering, Long, Thomas J, Griffith, Linda G, Cosgrove, P. A., Dunn, R. T., Stolz, D. B., Hamadeh, H., Afshari, C., McBride, H., Massachusetts Institute of Technology. Biotechnology Process Engineering Center, Massachusetts Institute of Technology. Department of Biological Engineering, Massachusetts Institute of Technology. Department of Mechanical Engineering, Long, Thomas J, Griffith, Linda G, Cosgrove, P. A., Dunn, R. T., Stolz, D. B., Hamadeh, H., Afshari, C., and McBride, H.

Abstract

Traditional in vitro human liver cell culture models lose key hepatic functions such as metabolic activity during short-term culture. Advanced three-dimensional (3D) liver coculture platforms offer the potential for extended hepatocyte functionality and allow for the study of more complex biologic interactions, which can improve and refine human drug safety evaluations. Here, we use a perfusion flow 3D microreactor platform for the coculture of cryopreserved primary human hepatocytes and Kupffer cells to study the regulation of cytochrome P450 3A4 isoform (CYP3A4) activity by chronic interleukin 6 (IL-6)-mediated inflammation over 2 weeks. Hepatocyte cultures remained stable over 2 weeks, with consistent albumin production and basal IL-6 levels. Direct IL-6 stimulation that mimics an inflammatory state induced a dose-dependent suppression of CYP3A4 activity, an increase in C-reactive protein (CRP) secretion, and a decrease in shed soluble interleukin-6 receptor (IL-6R) levels, indicating expected hepatic IL-6 bioactivity. Tocilizumab, an anti-IL- 6R monoclonal antibody used to treat rheumatoid arthritis, has been demonstrated clinically to impact small molecule drug pharmacokinetics by modulating cytochrome P450 enzyme activities, an effect not observed in traditional hepatic cultures. We have now recapitulated the clinical observation in a 3D bioreactor system. Tocilizumab was shown to desuppress CYP3A4 activity while reducing the CRP concentration after 72 hours in the continued presence of IL-6. This change in CYP3A4 activity decreased the half-life and area under the curve up to the last measurable concentration (AUClast) of the small molecule CYP3A4 substrate simvastatin hydroxy acid, measured before and after tocilizumab treatment. We conclude that next-generation in vitro liver culture platforms are well suited for these types of long-term treatment studies and show promise for improved drug safety assessment., United States. Defense Advanced Research Projects Agency (W911NF-12-2-0039), National Institutes of Health (U.S.) (UH3TR000496)

Published
2018

32. Production scale MOCVD growth of II–VI semiconductors

Author

Söllner, J., primary, Deschler, M., additional, Jürgensen, H., additional, Kalisch, H., additional, Taudt, W., additional, Hamadeh, H., additional, Heuken, M., additional, Blieske, U., additional, Saad, M., additional, Bauknecht, A., additional, Kampschulte, T., additional, Albert, J., additional, and Lux-Steiner, M.Ch., additional

Published
1998
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50. Effects of pomegranate juice supplementation on pulse wave velocity and blood pressure in healthy young and middle-aged men and women.

Author

Lynn A, Hamadeh H, Leung WC, Russell JM, Barker ME, Lynn, Anthony, Hamadeh, Hiba, Leung, Wing Chi, Russell, Jean M, and Barker, Margo E

Abstract

Pomegranate juice may improve cardiovascular risk because of its content of antioxidant polyphenols. We conducted a randomized placebo-controlled parallel study to examine the effect of pomegranate juice on pulse wave velocity (PWV), blood pressure (BP) and plasma antioxidant status (ferric reducing power; FRAP) in 51 healthy adults (30-50 years). Participants consumed 330 ml/day of pomegranate juice or control drink for four weeks. Measurements were made at baseline and at four weeks. There was no effect of the intervention on PWV (P = 0.694) and plasma FRAP (P = 0.700). However, there was a significant fall in systolic blood pressure (-3.14 mmHg, P < 0.001), diastolic blood pressure (-2.33 mmHg P < 0.001) and mean arterial pressure (-2.60 mmHg, P < 0.001). Change in weight was similar in the two groups over the intervention period (P = 0.379). The fall in BP was not paralleled by changes in concentration of serum angiotensin converting enzyme. We conclude that pomegranate juice supplementation has benefits for BP in the short term, but has no effect on PWV. The mechanism for the effect is uncertain. [ABSTRACT FROM AUTHOR]

Published
2012

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